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N-acetylserotonin and the hypotensive effect of MAO-A inhibitors

Abstract: Vladimir Zinovievich Gorkin's theory of the transformation of catalytic activity of amine oxidases and, therweby, selectivity of amine oxidases, carried over from my personal acquaintance with Vladimir Zinovievich, significantly influenced our studies into the mechanism of MAO-induced stimulation of pineal melatonin biosynthesis from serotonin. We found that this effect depended on the selective inhibition of MAO-A, but not MAO-B, which resulted in the increased formation of N-acetylserotonin (N-AS), the intermediate precursor of melatonin. The hypotensive effect of clorgyline was attenuated by pinealectomy, suggesting that increased N-AS and/or production might contribute to the hypotensive effect of selective MAO-A inhibition. Basal and isoproterenol-induced pineal levels of N-AS, but not melatonin, were lower in 12 week old (hypertensive) than in 4 week old (normotensive) spontaneously hypertensive (SHR) rats. N-AS decreased blood pressure in 12 week old SHR rats. The hypotensive effect of N-AS was augmented by pinealectome and by pretreatment with the S-adenosylhomocysteine, the inhibitor of N-AS conversion into melatonin. Our data demonstrate that hypotensive effect of N-AS is independent of its conversion to melatonin. We suggest that hypotensive effect of selective MAO-A inhibition might depend on the increased formation of N-AS, but not melatonin. The age-associated decrease in N-AS production may contribute to the developing of hypertension in SHR rats, and the age-associated increase of blood pressure in humans. Our data warrant the clinical trial of N-AS for the treatment of essential hypertension.